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DISC1 2010—From Transcription to Prefrontal Cortex via Insoluble Aggregates and Dopamine

As part of our ongoing coverage of DISC1 2010, held 3-6 September 2010 in Edinburgh, the United Kingdom, we bring you a meeting missive from Elise Malavasi, a graduate student at the University of Edinburgh.


29 September 2010. Carsten Korth from the University of Dusseldorf, Germany, was the first speaker of the two sessions on Sunday afternoon dedicated to the biochemistry and pharmacology of DISC1. After his introduction by session chair Nick Brandon of Pfizer Inc., Korth presented new evidence supporting a role for the aggregation of non-mutant DISC1 protein in the pathogenesis of a subset of sporadic cases of schizophrenia (see coverage in SRF meeting report). Korth reported that, in addition to S704C, another SNP located in the C-terminus of DISC1, L607F, affects the propensity of DISC1 to form multimers and might therefore disturb DISC1 binding to Ndel1. In accordance with these findings, in a poster that I (Elise Malavasi) and my colleagues from the University of Edinburgh presented at the meeting, L607F was found to profoundly disrupt the association of DISC1 with the cytoskeleton in a transfected cell system. Korth went on to present new, intriguing evidence for a pathogenic role of DISC1 aggregates. He and colleagues found that in a large proportion of the diseased brains that tested positive for insoluble DISC1, dysbindin 1 was also present in the insoluble fractions. Further studies in transfected cell lines strengthened the hypothesis that by sequestering dysbindin 1 in insoluble aggregosomes, DISC1 might interfere with its normal function.

Patricio O’Donnell from the University of Maryland, Baltimore, illustrated the role of dopaminergic neurons in the regulation of the synaptic responses in pyramidal cells. O’Donnell put particular emphasis on the notion that the control of cortical glutamatergic and GABAergic circuits by dopamine matures during adolescence, and argued that the loss of such maturation is likely to underlie the peri-adolescent onset of behavioral abnormalities observed in animals that received brain lesions prenatally (see SRF related news story). Consistent with this hypothesis, O’Donnell and colleagues reported that DISC1 knockdown in prenatal or early postnatal animals induces behavioral and physiological abnormalities that emerge only after puberty. Of interest, such anomalies are accompanied by incomplete maturation of dopaminergic circuits (see SRF related news story). In a related poster, Ross Caldarelli, a member of O’Donnell’s lab, presented more evidence supporting a role for DISC1 in the maturation of dopamine circuits. He observed that the peri-adolescent maturation of D2-mediated effects in the medial prefrontal cortex is attenuated in adult mice expressing truncated DISC1 under the αCaMKII promoter compared to wild-type. In light of these findings, O’Donnell proposed a model whereby genetic susceptibility combined with environmental insults early in development generates synaptic anomalies in the cortex, resulting in labile interneurons. Only at puberty does the lack of proper maturation of dopaminergic neurons cause these anomalies to manifest at the behavioral level.

Next on the podium was Nick Bray from the Institute of Psychiatry, U.K., who shifted the attention to the role of DISC1 in transcriptional control. Bray studied the effect of DISC1 knockdown on the transcriptome of immortalized human neural cells. He emphasized the validity of these cells as a tool to study neuronal-specific transcriptional regulation, as they are euploid, nestin positive, and they express all four major DISC1 isoforms. By specifically targeting exon 7, Bray and colleagues knocked down the long, long variant and short isoforms of DISC1, but not the extra short, mimicking the effect of the 1:11 translocation. Using an Illumina platform, they identified several genes that were specifically up- or downregulated by DISC1, and 15 of these were replicated and confirmed by qPCR. Bray concluded by remarking that the changes in expression levels he detected are quite modest, but the pool of DISC1 transcriptional targets is enriched for genes associated with bipolar and/or schizophrenia, reinforcing the role of DISC1 in the pathophysiology of these disorders.

The last talk of the session, delivered by Korth's colleague in Dusseldorf, Verian Bader, brought the focus back to the pathophysiological role of insoluble DISC1 aggregates. Bader presented new data indicating that dopamine can affect the solubility of DISC1. Bader used amphetamine sensitization as an in vivo model of deregulated dopamine metabolism, and found that insoluble DISC1 is enriched in the mPFC and depleted from the striatum of d-amphetamine-sensitized rats compared to controls. Furthermore, he observed an inverse relationship between the amount of insoluble DISC1 in the mPFC and the travel distance of the animals, used to quantify the behavioral response to d-amphetamine. Bader remarked that the opposing changes induced by d-amphetamine on dopamine levels in the mPFC (increase) and striatum (decrease) are mirrored by same-direction alterations of the abundance of insoluble DISC1 in the same brain areas. To further test the hypothesis that dopamine affects the solubility of DISC1, Bader exposed DISC1-transfected neuroblastoma cells to increasing concentrations of dopamine, and indeed found a direct relationship between dopamine levels and insoluble DISC1. In addition, he observed that treating DISC1-overexpressing cells with dopamine leads to a decreased interaction between soluble DISC1 and its binding partner NDEL1. In conclusion, Bader’s data indicate that there is a direct relationship, both in vivo and in vitro, between dopamine levels and insoluble DISC1, suggesting that the abnormal accumulation of insoluble DISC1 aggregates in a subset of schizophrenic brains could be a direct consequence of dysfunctional dopamine metabolism.—Elise Malavasi.

 
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